Idiopathic Parkinson""s Disease (IPD) is a progressive neurodegenerative disorder. The onset of IPD symptoms begin to manifest when a threshold reduction of 60%-70% nigral neurons accompanied by an 80%-90% attenuation in striatal dopamine efflux, has been reached (Koller, W. C., xe2x80x9cWhen does Parkinson""s disease begin?xe2x80x9d, (1992) Neurology 42(S4):27-31). Symptoms include tremor, postural imbalance, rigidity, bradykinesia and akinesia (Diagnostic Clinical Neuropsychology, Bigler, E. and Clement, P., Eds., 3rd Ed. 1997). These symptoms intensify as the disease progresses. In severe stages of IPD, following the onset of akinesia, even the simplest movements require a monumental degree of concentration and mental effort, often to the point of anguish (Textbook of Medical Physiology, Guyton, A. C. and Hall, J. E., Eds., 9th Ed., W. B. Saunders Company, Philadelphia, Pa., 1996). IPD is also characterized by a number of autonomic (Vainshtok, A. B., xe2x80x9cTreatment of Parkinsonism with delagil,xe2x80x9d (1972) Klin. Med (Mosk) 50(9):51-56) and non-motor symptoms including depression (Cummings, J. L., xe2x80x9cDepression and Parkinson""s Disease: A Review,xe2x80x9d (1992) Am. J. Psychiatry 149(4):443-454) and frontal lobe dysfunction (Gotham, A. M. et al., xe2x80x9cLevodopa treatment may benefit or impair xe2x80x98frontalxe2x80x99 function in Parkinson""s disease,xe2x80x9d (1986) Lancet 25;2(8513):970-971).
In the United States, it is estimated that 5-24 in every 100,000 people suffer from IPD, with the majority of low income cases going undiagnosed (Chrischilles, E. A. et al., xe2x80x9cThe health burdens of Parkinson""s disease,xe2x80x9d (1998) Movement Disorders 13(3):406-413 ). In 1995, the World Health Organization conducted a global epidemiological evaluation of the incidence of IPD, showing a worldwide incidence of 5.32 per 100,000 people with an astounding incidence rate of 49.33 per 100,000 people over the age of 65 (M. Privett, WHO). Although more recent epidemiological figures are unavailable, in 1996 with the world population being approximately 5.7 billion, an estimated 2.8 million people had a confirmed diagnosis of IPD.
Current pharmacological treatments for IPD and other Parkinsonian-like motor disorders include anticholinergic agents, catechol-o-methyltransferase inhibitors and dopaminergic agents (Physicians"" Desk Reference, 2000, 54th Ed., Medical Economics Company, Inc., Montvale, N.J.). Since the late sixties, dopamine precursor L-DOPA, has been employed for the symptomatic relief of IPD motor dysfunction (Mena, M. A. et al., xe2x80x9cPharmacokinetics of L-DOPA in patients with Parkinson""s disease,xe2x80x9d (1986) Advances in Neurology 45:481-486). However, following long term use of L-DOPA (generally 5-8 years), diminished therapeutic efficacy is observed in approximately 50% of IPD patients (Roos, R. A. et al., xe2x80x9cResponse fluctuations in Parkinson""s disease,xe2x80x9d (1990) Neurology 40(9): 1344-1346). A wearing off of L-DOPA efficacy precedes the development of serious motor side effects such as on/off motor oscillations and dyskinesias (Carlsson, Arvid, xe2x80x9cDevelopment of new pharmacological approaches in Parkinson""s disease,xe2x80x9d (1986) Advances in Neurology 45:513-518). Further, when medications are increased to compensate for the development of these new motor dysfunctions, more serious side effects are generally observed, including psychiatric complications, while producing only minimal therapeutic benefit (Stoof, J. C. et al., xe2x80x9cLeads for the development of neuroprotective treatment in Parkinson""s disease and imaging methods for estimating treatment efficacy,xe2x80x9d (1999) Eur. J. Pharmacol. 375(1-3):75-86).
Deprenyl, a monoamine oxidase (MAO) B inhibitor, was the first drug suggested to provide causal treatment of Parkinson""s Disease by alleviating symptoms and attenuating the progression of the illness (Mytilineou, C. et al., xe2x80x9cL-(xe2x88x92)-desmethylselegiline, a metabolite of selegiline [L-(xe2x88x92)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro,xe2x80x9d (1997) J. Neurochemistry 68(1):434-436). However, there remains much controversy regarding the therapeutic efficacy of Deprenyl. While some physicians prefer to prescribe Deprenyl when patients first present with symptoms of Parkinson""s Disease (Goldstein, M. and Lieberman, A., xe2x80x9cThe role of the regulatory enzymes of catecholamine synthesis in Parkinson""s disease,xe2x80x9d (1992) Neurology 42(S4):8-12), other physicians dispute claims of neural protection (Olanow, C. W. and Calne, D., xe2x80x9cDoes selegiline monotherapy in Parkinson""s disease act by symptomatic or protective mechanisms?xe2x80x9d (1992) Neurology 42(S4):13-26).
Poewe and Wenning (Poewe, W. H. and Wenning, G. K., xe2x80x9cThe natural history of Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(S1):S1-S9) reviewed several longitudinal studies which evaluated Parkinson""s Disease medications. The Parkinson""s Research Group of the United Kingdom found that when Deprenyl was co-administered with L-DOPA, a 60% increase in patient mortality was observed, compared to the group being treated with L-DOPA only. Deprenyl is now rarely prescribed by European physicians for the treatment of IPD. In contrast, American researchers determined that Deprenyl is capable of delaying the need to commence L-DOPA treatment for a period of up to nine months. However, no neural protection was found in two-year patient follow-up examinations (Poewe and Wenning, 1998, supra). In Parkinson""s Disease the average lifespan is 9.4 years following an initial diagnosis. Further, the onset of gait disorders is closely associated with mortality rate. To be superior to current causal treatments (i.exe2x80x94Deprenyl), a pharmacological treatment must: a) prolong the need to commence L-DOPA for more than nine months; b) retain efficacy beyond a two-year period; and, c) prevent, delay, or otherwise alleviate gait disorders.
Up to 20% of the people initially diagnosed with IPD, actually suffer from atypical IPD (APD), striatonigral degeneration (SND), or multiple symptom atrophy (MSA) (Antonini, A. et al., xe2x80x9cDifferential diagnosis of Parkinsonism with [18F]Fluorodeoxyglucose and PET,xe2x80x9d (1998) Movement Disorders 13(2):268-274). Little or no response to conventional Parkinson""s Disease drug therapy is usually the differentiating factor between a diagnosis of APD, SND and MSA as opposed to IPD (Dethy, S. et al., xe2x80x9cAsymmetry of basal ganglia glucose metabolism and dopa responsiveness in Parkinsonism,xe2x80x9d (1998) Movement Disorders 13(2):275-280). Often, little can be done for people suffering these atypical afflictions. Therefore, it would be of great benefit if a pharmacological means were identified that could alleviate symptoms of atypical Parkinson""s Disease, as well as IPD.
The exact cause or causes of IPD are still unknown. Nonetheless, scientists have discovered a multitude of pathological abnormalities in the Parkinsonian brain. These findings include but are not limited to: a) toxic metabolite formation during neuromelanin (NM) synthesis (Graham, D. G., xe2x80x9cAutoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitroxe2x80x9d (1978) Molecular Pharmacology 14:644-653); b) heightened affinity of endogenous and exogenous toxins for NM (Tipton, K. F. and Singer, T. P., xe2x80x9cAdvances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds,xe2x80x9d (1993) J. Neurochem. 61(4):1191-1206); c) mitochondrial impairment (Mizuno, Y. et al., xe2x80x9cMitochondrial dysfunction in Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(S1):S99-S109); d) increased oxidative stress potentiated by reduced levels of antioxidants (Merad-Boudia, M. et al., xe2x80x9cMitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson""s disease,xe2x80x9d (1998) Biochem. Pharmacology 56:645-655); e) protein oxidation and lipid peroxidation (Jenner, P. et al., xe2x80x9cUnderstanding cell death in Parkinson""s disease,xe2x80x9d (1998) Annals of Neurology 44(1):S72-S84); f) augmented iron content and abnormal Fe(II)/Fe(III) ratios (Riederer, P. et al., xe2x80x9cTransition metals, ferritin, glutathione, and ascorbic acid in Parkinsonian brains,xe2x80x9d (1989) J. Neurochemistry 52(2):515-520); and g) the accumulation of extracellular protein peptide fragments (Loo, D. T. et al., xe2x80x9cApoptosis is induced by xcex2-amyloid in cultured central nervous system neurons,xe2x80x9d (1993) Proc. Natl. Acad. Sci. USA 90:7951-7955). An example of these extracellular amyloid peptide fragments are the non-Axcex2 components in Lewy bodies (Culvenor, J. G. et al., xe2x80x9cNon-Axcex2 component of Alzheimer""s disease amyloid (NAC) revisited,xe2x80x9d (1999) Am. J. Pathology 155:1173-1181) which trigger an apoptotic cascade. Taken individually, these pathological findings would not pose a tremendous cellular threat. Collectively and occurring simultaneously, they serve to progressively annihilate the melanized catecholamine neurons residing in the mesencephalon, ultimately producing the classic signs of Parkinson""s Disease.
Chloroquine Compounds
Chloroquine [7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline] (The Merck Index, p. 2220, 1996) is a synthetically manufactured anti-malarial containing the quinoline nucleus. Chloroquine was developed over fifty years ago. It continues to be the most widely employed drug for the treatment of the asexual erythrocytic form of P. falciparum (Deepalakshmi, P. D. et al., xe2x80x9cEffect of chloroquine on rat liver mitochondria,xe2x80x9d (1994) Indian J. Exp. Biology 32(11):797-799). Unfortunately, due to widespread use of chloroquine, treatment resistant stains of malaria, first reported in 1961, continue to emerge globally, making the use of chloroquine obsolete in many regions (Bitonti, A. J. et al., xe2x80x9cReversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine,xe2x80x9d (1988) Science 241:1301-1303). A number of chloroquine derivates have been identified for antimalarial and other use. See U.S. Pat. Nos. 5,948,791, 5,834,505, 5,736,557, 5,639,737, 5,624,938, 5,596,002 and 4,421,920.
Due to the widespread use of chloroquine, a number of beneficial therapeutic properties and medicinal applications, outside of conventional malarial treatment, have been identified. Most of the following studies employed chloroquine phosphate.
Chloroquine phosphate is a potent inhibitor of acid chondromucoprotease present in cartilage and of cathepsin B1, a protease especially important in the initiation of proteolysis (De Duve, C. et al., xe2x80x9cLysosomotropic agents,xe2x80x9d (1974) Biochem. Pharm. 23:2495-2531). These properties have rendered chloroquine phosphate useful in the treatment of rheumatoid arthritis (Clinical Toxicology, supra, Section III, pp. 355-362). Further, chloroquine phosphate is known to reduce hypertension (Physician""s Desk Reference, pp. 2301-2302, 1996). Chloroquine phosphate and other 4-aminoquinoline compounds have been prescribed for the treatment of cardiac arrhythmia (Clinical Toxicology, supra, Section III, pp. 355-362). A version of antimalarial drug called Cardioquin(copyright) is produced by the Purdue Fredrick Company for the maintenance of sinus rhythm after conversions from atrial fibrillation (Physician""s Desk Reference, pp. 2521-2522, 2000). Chloroquine phosphate also targets malignant metastatic melanomas that generally bear an accumulation of melanin. The utilization of chloroquine phosphate for the treatment of these tumors is limited by the lack of accumulation in the amelanotic forms that readily manifest (Lindquist, N. G., xe2x80x9cAccumulation of drugs on melanin,xe2x80x9d (1973) Acta Radiol. Diag. (Stockholm) 325:1-92). A more recent application of chloroquine phosphate is to suppress the human immunodeficiency virus type 1 (HIV-1) replication in vivo within T-cells and monocytes (Sperber, K. et al., xe2x80x9cHydroxychloroquine treatment of patients with human immunodeficiency virus type 1,xe2x80x9d (1995) Clinical Therapeutics 17(4):622-636; Ornstein, M. H. and Sperber, K., xe2x80x9cThe anti-inflammatory and antiviral effects of hydroxychloroquine in two patients with acquired immunodeficiency syndrome and active inflammatory arthritis,xe2x80x9d (1996) Arthritis Rheum. 39(1):157-161).
The above medicinal applications of chloroquine phosphate are generally known to those practicing medicine in the USA. The following applications of chloroquine phosphate have been discovered and successfully employed by doctors throughout the world. Chloroquine phosphate has been used to treat renal disorders such as glomerulonephritis and amyloidosis, with observed improvement in renal function and attainment of various lengths of remission (Makarenko, I. E. and Levitsky, E. P., xe2x80x9cResoquin in the clinic of internal illnesses, and the possible side effects of its use,xe2x80x9d (1950). A randomized trial of the prolonged use of chloroquine phosphate to treat advanced pulmonary sarcoidosis, suggests that patients responded better to chloroquine phosphate and withstood medication side effects better than with conventional corticosteroids (Baltzan, M. et al., xe2x80x9cRandomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis,xe2x80x9d (1999) Am. J. Respir. Crit. Care Med. 160:192-197). Conditions of acute hypertension can benefit from the administration of chloroquine phosphate, which acts as a vasodilator without depressing cardiac contractibility (Abiose, A. K. et al., xe2x80x9cChloroquine-induced venodilation in human hand veins,xe2x80x9d (1997) Clin. Pharm. and Therapeutics 61(6):677-683). Chloroquine phosphate inhibits lysosomal proteolysis in vitro, and has been suggested to be a useful agent in counteracting protein wasting observed in several catabolic diseases (De Feo, P. et al., xe2x80x9cChloroquine reduces whole body proteolysis in humans,xe2x80x9d (1994) Am. J. Physiology 267:E183-E186). Chloroquine phosphate inhibits the biological availability of iron and has been suggested as advantageous for the treatment of iron-loading disorders (Legssyer, R. et al., xe2x80x9cEffect of chronic chloroquine administration on iron loading in the liver and reticuloendothelial system and on oxidative responses by the alveolar macrophages,xe2x80x9d (1999) Biochem. Pharmacology 57(8):907-91 1). Several case histories have been published regarding the efficacy in administering chloroquine phosphate to infants suffering from desquamative interstitial pneumonitis who presented with failure to thrive, tachypnea and hypoxia (Springer, C. et al., xe2x80x9cChloroquine treatment in desquamative interstitial pneumonia,xe2x80x9d (1987) Archives of Disease in Childhood 62:7677), and were non-respondent to steroids (Leahy, F. et al., xe2x80x9cDesquamative interstitial pneumonia responsive to chloroquine,xe2x80x9d (1985) Clinical Pediatrics 24(4):230-232).
Further recognized, but non-FDA approved, uses of chloroquine phosphate include treatments for: cholera, idiopathic pulmonary hemosiderosis, lupus erythematosus, lymphoid interstitial pneumonitis, onchocerca volvulus, porphyria cutanea tarda, m. sarcoidosis, and ulcerative colitis (MICROMEXEX(copyright), 2000, available: http//phamtom.uchsc.edu/mdxcgi/di). U.S. Pat. No. 5,430,039 suggests the use of chloroquine to inhibit neuronal cell death resulting from a calcium-related disorder of the central or peripheral nervous system, erroneously characterizing Parkinson""s Disease as such a disorder. Vainshtok, A. B., xe2x80x9cTreatment of Parkinsonism with delagil,xe2x80x9d (1972) Klin. Med (Mosk) 50(9):51-56, reports administration of Delagil, a chloroquine compound or analog (exact compound unknown) to a group of medication-free patients (dosage unknown) suffering symptoms related to Parkinson""s disease with moderate to dramatic response.
Enantiomers of Chloroquine
Chloroquine and hydroxychloroquine are racemic mixtures of (xe2x88x92)- and (+)-enantiomers. The (xe2x88x92)-enantiomers are also known as (R)-enantiomers (physical rotation) and 1-enantiomers (optical rotation). The (+)-enantiomers are also known as (S)-enantiomers (physical rotation) and r-enantiomers (optical rotation). The (+)-enantiomer metabolizes peripherally about eight times more rapidly than the (xe2x88x92)-enantiomer, producing toxic metabolites including de-ethyl chloroquine (Augustijins, P. and Verbeke, N. [1993] xe2x80x9cStereoselective pharmacokinetic properties of chloroquine and de-ethyl chloroquine in humans,xe2x80x9d Clinical Pharmacokinetics 24(3):259-69; Augustijins, P. et al. [1999], xe2x80x9cStereoselective de-ethylation of chloroquine in rat liver microsomes,xe2x80x9d Eur. J. Drug Metabolism and Pharmacokinetics 24(1):105-8; DuCharme, J. and Farinotti R. [1996], xe2x80x9cClinical pharmacokinetics and metabolism of chloroquine,xe2x80x9d Clinical Pharmacokinetics 31(4):257-74). Administering (+)-chloroquine may cause cardiac side effects due to toxic metabolite formation. The (xe2x88x92)-enantiomer has a longer half-life and lower clearance than the (+)-enantiomer (Ducharme, J. et al. (1995), xe2x80x9cEnantio-selective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects,xe2x80x9d British J. Clinical Pharmacology 40(2):127-33). The enantiomers of chloroquine and hydroxychloroquine may be prepared by procedures known to the art.
All publications referred to herein are incorporated by reference to the extent not inconsistent herewith.
This invention provides compositions and methods for increasing cellular respiration of melanized catecholamine neurons such as dopamine neurons in the substantia nigra, epinephrine and norepinephrine neurons, of protecting such neurons against oxidative degradation, and for treatment of Parkinson""s Disease, including both alleviation of symptoms and preventing onset or progression of symptoms. The compositions of this invention may be administered long-term. The compositions of this invention are also useful for preventing on-off syndrome, a condition in which L-Dopa and other dopamine agonists temporarily or permanently lose their ability to ameliorate the symptoms of Parkinson""s Disease after an initial period of effectiveness.
The term xe2x80x9cCQxe2x80x9d includes chloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), chloroquine phosphate (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline phosphate, and hydroxychloroquine (7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline), and mixtures thereof. Similarly, the terms (xe2x88x92)-chloroquine and (+)-chloroquine include (xe2x88x92)- and (+)-chloroquine phosphate and (xe2x88x92)- and (+)-hydroxychloroquine respectively.
Compositions useful for increasing cellular respiration of melanized catecholamine neurons, and/or alleviating, preventing or halting progress of Parkinson""s symptoms comprise neuromelanin-binding chloroquine analogs and derivatives containing a quinoline nucleus, preferably selected from the group consisting of:
7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline (chloroquine);
7-hydroxy-4-(4-diethylamino-1-methylbutylamino)quinoline; chloroquine phosphate;
7-chloro-4-(4-diethylamino-1-butylamino)quinoline (desmethylchloroquine);
7-hydroxy-4-(4-diethylamino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-diethylamino-1-methylbutylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-diethylamino-1-methylbutylamino)quinoline;
7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline (hydroxychloroquine);
7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline; hydroxychloroquine phosphate;
7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline (desmethylhydroxychloroquine);
7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;
7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;
7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;
8-[(4-aminopentyl)amino]-6-methoxydihydrochloride quinoline;
1-acetyl-1,2,3,4-tetrahydroquinoline; 8-[4-aminopentyl)amino]-6-methoxyquinoline dihydrochloride;
1-butyryl-1,2,3,4-tetrahydroquinoline; 7-chloro-2-(o-chlorostyryl)-4-[4-diethylamino-1-methylbutyl]aminoquiinoline phosphate;
3-chloro-4-(4-hydroxy-xcex1,xcex1xe2x80x2-bis(2-methyl-1-pyrrolidinyl)-2,5-xylidinoquinoline, 4-[(4-diethylamino)-1-methylbutyl)amino]-6-methoxyquinoline;
3,4-dihydro-1 (2H)-quinolinecarboxyaldehyde;
1,1xe2x80x2-pentamethylenediquinoleinium diiodide; and 8-quinolinol sulfate, enantiomers thereof, said compounds covalently linked or complexed or mixed with targeting agents, and mixtures thereof, as well as suitable pharmaceutical salts thereof. Chloroquine and hydroxychloroquine are preferred; (xe2x88x92)-enantiomers thereof are more preferred, and said compounds covalently linked or complexed or mixed with targeting agents are most preferred. Neuromelanin-binding compounds such as chlorpromazine and other antipsychotics which bind to dopamine receptors are not included within the scope of PD-effective neuromelanin-binding compounds of this invention. Any chloroquine analog or derivative known to the art and capable of binding neuromelanin may be useful in the methods of this invention.
Preferably the neuromelanin-binding compound is selected from the group consisting of compounds capable of crossing the blood-brain barrier in effective amounts. Such compounds include those which are more lipophilic, are capable of changing to effective chirality after crossing the blood-brain barrier, have side chain substituents which enhance compound transport via blood-brain barrier transporter mechanisms, or are complexed or covalently linked with antibodies or other targeting moieties, or administered in combination with other compounds facilitating their crossing the blood-brain barrier, as known to the art. The (xe2x88x92)-enantiomer of chloroquine (referred to herein as the active enantiomer) is preferred.
In a preferred embodiment, the compositions useful for increasing cellular respiration of melanized catecholamine neurons comprise an effective amount of a composition comprising (xe2x88x92)-CQ or (xe2x88x92)-CQ mixed, complexed or covalently linked with a targeting agent; an amount of (+)-CQ less than that of said (xe2x88x92)-CQ or (xe2x88x92)-CQ complexed or covalently linked with a targeting agent; and a suitable pharmaceutical carrier.
A targeting agent is a substance that when complexed with the CQ helps carry it across the blood brain barrier. Preferred targeting agents are lipophilic moieties known to the art which are attached to the active molecule at a position which does not interfere with the ability of the quinoline ring to bind to neuromelanin, and antibodies such as an antibody capable of binding to the transferrin receptor on brain capillary cells, e.g., as described in U.S. Pat. No. 6,015,555, incorporated herein by reference to the extent not inconsistent herewith.
Such compositions containing (xe2x88x92)-chloroquine may include anywhere from no (+)-CQ to about 49% (+)-CQ. An amount of (+)-CQ sufficient to bind to enzymes causing peripheral breakdown of CQ is preferred, leaving more of the (xe2x88x92)-CQ to cross the blood brain barrier where its therapeutic effect takes place. Preferably the compositions comprise between about 10% and about 20% (+)-CQ.
In one embodiment, a single adult dosage amount of said composition effective for increasing cellular respiration of melanized catecholamine neurons is provided, preferably less than an antimalarial single adult dosage amount, more preferably less than about 1 mM base equivalent, and most preferably less than about 0.5 mM base equivalents of CQ. As is known to the art, the term xe2x80x9cbase equivalentsxe2x80x9d refers to amount of active ingredient (e.g., in reference to chloroquine phosphate, refers to the chloroquine minus the phosphate and filler components). A single adult dosage amount with respect to use for alleviation, preventing or stopping progression of symptoms of Parkinson""s Disease or for other uses will be an amount effective when administered daily to provide the stated therapeutic effect.
Compositions of this invention may also comprise an effective amount of at least one adjuvant selected from the group consisting of antioxidants, retinal protective agents, other neural protective compounds, dopamine or dopamine agonists, and free radical deactivators. The antioxidant may be any antioxidant known to the art to prevent free radical formation and oxidative degradation of tissues and is preferably selected from the group consisting of probucol, pyncnogenol, Vitamin C, Vitamin E, superoxide dismutase, preferably synthetic, BHT, BHA, and melatonin. The retinal protective agent is preferably a composition administered locally to prevent binding of retinal melanin with the CQ, as is known to the art, e.g., alkanes and alcohols of C1-C4, and ginko biloba. The neural protective compound is any compound known to the art and preferably is selected from the group consisting of selegiline hydrochloride and other monoamine oxidase inhibitors. The dopamine agonist is any compound known to the art as an anti-Parkinson""s treatment and preferably is selected from the group consisting of L-DOPA, pramipexole, ropinerole, bromocriptine, tolcapone, and carbidopa. The free radical deactivator is any compound known to the art and preferably is selected from the group consisting of superoxide dismutase, selegiline, hydrochloride, and tolcapone.
This invention also provides kits comprising in close proximity, such as in a container or blister pack, effective dosage amounts and forms of the compositions of this invention for single doses, or doses per week, or other appropriate time period, preferably in combination with an adjuvant, such as an antioxidant, dopamine or dopamine agonist, or other adjuvant as discussed above suitable for co-administration with said composition, in effective dosage forms and amounts.
Suitable pharmaceutical carriers are known to the art and include carriers aiding in transport across the blood/brain barrier, such as nanoparticles onto which the compositions are absorbed, coated with a detergent, e.g., as described in Begley, D. J. (1996) xe2x80x9cThe blood-brain barrier: principles for targeting peptides and drugs to the central nervous system,xe2x80x9d J. Pharm. Pharmacol. 48(2):136-46, incorporated herein by reference to the extent not inconsistent herewith.
This invention also provides methods for increasing cellular respiration of melanized catecholamine neurons, and methods for alleviating symptoms or stopping appearance and/or progression of symptoms of Parkinson""s Disease, and methods for preventing symptoms of on-off syndrome associated with treatment with dopamine or a dopamine agonist of a patient suffering symptoms of a disease selected from the group consisting of idiopathic and atypical Parkinson""s disease, conditions characterized by nigrostriatal degeneration, multiple system atrophy, and vascular Parkinson""s Disease, said methods comprising administering to said patient an effective amount of the above composition of this invention. The methods are suitable for any mammal having such melanized neurons or symptoms of Parkinson""s Disease. Methods for treating or preventing symptoms of Parkinson""s Disease also comprise identifying patients having such symptoms or at risk of developing them.
Further provided are methods of making pharmaceutical compositions effective for increasing cellular respiration of melanized catecholamine neurons comprising: providing a compound or complex of this invention as described above, providing a suitable pharmaceutical carrier; and mixing said compound or complex and pharmaceutical carrier to form a composition effective to increase cellular respiration of melanized catecholamine neurons.
Instead of mixing (+)-CQ with (xe2x88x92)-CQ, the method of making the compositions of this invention comprising (xe2x88x92)-CQ may be practiced by starting with racemic chloroquine and removing an amount of (+)-CQ to leave a CQ composition effective to increase cellular respiration of melanized catecholamine neurons.
The term xe2x80x9cincreasing cellular respirationxe2x80x9d means measurably increasing oxygen consumption, increasing aerobic cellular respiration and reducing anaerobic cellular respiration, e.g., as measured by lactate in the cerebral spinal fluid.
The term xe2x80x9cdiminishing oxidative degradation of dopamine neurons in the substantia nigraxe2x80x9d means measurably diminishing such degradation as measured by assays known to the art, including measures of free iron ion availability and oxygenated radical formation.
The term xe2x80x9cParkinson""s Diseasexe2x80x9d as used herein includes idiopathic Parkinson""s Disease (IPD), atypical Parkinson""s Disease (APD), striatonigral degeneration (SND), multiple symptom atrophy (MSA), and vascular Parkinson""s Disease.
The term xe2x80x9calleviating symptoms of Parkinson""s Diseasexe2x80x9d means measurably reducing, inhibiting, attenuating and/or compensating for at least one symptom of Parkinson""s disease, such as tremor, postural imbalance, rigidity, bradykinesia, akinesia, gait disorders, and on/off fluctuations. These symptoms may result from toxic metabolite formation during neuromelanin (NM) synthesis, heightened affinity of endogenous and exogenous toxins for NM, mitochondrial impairment, increased oxidative stress potentiated by reduced levels of antioxidants, protein oxidation and lipid peroxidation, augmented iron content and abnormal Fe(II)/Fe(III) ratios, and the accumulation of extracellular protein peptide fragments, which conditions may also be alleviated by the compositions of this invention.
The compositions of this invention containing (xe2x88x92)-CQ should have more (xe2x88x92)-CQ or (xe2x88x92)-CQ mixed, complexed or covalently linked with a targeting agent than (+)-CQ because the toxic metabolites of (+)-CQ make it less suitable for long-term use, and the better melanin-binding properties of (xe2x88x92)-CQ, its longer half life, and lower clearance make it more effective for long-term administration (e.g. at least about six weeks, more preferably, about two years, and most preferably, at least about ten years or more).
An effective amount of the compositions of this invention is an amount necessary to produce a measurable effect. For example, an effective amount of the compositions of this invention to increase cellular respiration measurably increases cellular respiration by assays known to the art as discussed above. In compositions containing (xe2x88x92)-CQ, the effect may be produced by the (xe2x88x92)-CQ, or partially by the (xe2x88x92)CQ and partially by (+) CQ. Similarly, an effective amount of a composition of this invention to alleviate or stop the progression of symptoms of Parkinson""s Disease is an amount which does so based on art-known tests such as the Unified Parkinson""s Disease Rating Scale and the Tinetti Gait and Balance Assessment Tool, comparing symptoms of treated patients with symptoms of the same patients prior to and/or after treatment, or with symptoms of untreated patients at the same stage of Parkinson""s Disease.
Preventing symptoms of Parkinson""s Disease includes identifying patients at risk for developing such symptoms. Identification of patients susceptible to onset of Parkinson""s Disease may be done by genetic testing, prediction from family history or other means known to the art such as PET scans. When symptoms of Parkinson""s do not develop, or do not develop to the expected (average) degree, they are considered to have been prevented by the methods and compositions of this invention.
Preventing on-off symptoms in patients being treated with L-Dopa or like medications means measurably stopping or decreasing such symptoms as compared with patients at similar stages of Parkinson""s Disease being treated with such medications.
The compounds of this invention may formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration. For example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
The effective dosage of active ingredient employed may vary depending on the particular mixture employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily adult dosage of from about 0.5 to about 1000 mg, optionally given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Preferably a single daily adult dose comprises less than about 1 mM, and more preferably less than about 0.5 mM base equivalents, more preferably less than about 1 mM, and more preferably less than about 0.5 mM base equivalents.
The compounds of this invention may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. In some cases it may be desirable to administer the compounds to the patient""s airways in the form of an aerosol.
The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
xe2x80x9cSuitable pharmaceutical carriersxe2x80x9d as referred to herein include distilled and pharmaceutical grade water but do not include water or buffers unsuitable for administration to a human patient.
There are several mechanisms by which neuromelanin may contribute to symptoms of Parkinson""s disease by contributing to formation of toxic products including superoxide and hydroxy radicals, which catalyze lipid peroxidation, and oxidation of NADH resulting in disruption of the neuron""s respiration and reducing the amount of energy available to the neurons via aerobic respiration.
Neuromelanin can be considered a waste product of catecholamine degradation and gradually accumulates within the cytosol of catecholamine neurons throughout one""s lifetime. Dopamine is autoxidized to cytotoxic and reactive oxygenated species such as 6-hydroxydopamine (6-OHDA) and semiquinone radicals. Low glutathione levels contribute to oxidative stress in Parkinson""s disease, and allow available hydrogen peroxide to be further catalyzed by iron into highly toxic superoxide radicals and hydroxyl radical species as well as semiquinone radicals. Dopamine and L-DOPA interaction with superoxide radicals augments depletion of glutathione, leading to a downward spiral of detrimental reactions.
Monoamine oxidase forms toxic metabolites from a number of substances such as beta-carboline derivatives and tetrahydroisoquinoline which are present in excessive amounts in the cerebral spinal fluid of people with Parkinson""s Disease. These toxic metabolites have high affinity to neuromelanin, and once bound may cause almost complete arrest of ATP production, resulting in impaired respiration, loss of energy available to the neurons and massive melanized cell loss which leads to symptoms of Parkinson""s Disease. Inhibitors of monoamine oxidase B such as Deprenyl prevent formation of these toxic metabolites. Iron also tends to bind to neuromelanin, resulting in a cascade of pathogenic reactions leading to neuronal death. Increasing iron concentrations in basal ganglia are observed with normal aging, and in patients with Parkinson""s Disease, iron is pathologically elevated with high ferric/ferrous ion ratios. The ferric ions contribute, with 6-OHDA, to the formation of harmful superoxide and hydroxyl radicals leading to lipid peroxidation and cell breakdown.
Iron chelators have been shown to reverse impaired mitochondrial respiration caused by 6-OHDA inhibition of NADH dehydrogenase. 6-OHDA catalyzes the release of iron from intracellular ferritin stores which in turn catalyzes lipid peroxidation. This toxic chain of events can be inhibited by superoxide dismutase. Both iron chelators and chloroquine phosphate have been found to limit the availability of free iron, so that it is not available to catalyze these toxic reactions.
The iron transporter protein, diferric transferrin, which delivers iron throughout the body also contributes to loss of energy available to the neurons by interfering with availability of reduced NADH. Chloroquine phosphate has been found to inhibit intracellular oxidation of NADH by melanin.
Chloroquine phosphate binds to neuromelanin and does not inhibit enzymatic synthesis of iron into biologically essential compounds. It not only prevents incorporation of iron into neurons, but also inhibits and release of iron from intracellular iron pools. In addition chloroquine phosphate has been found to heighten an astrocytic immune response against accumulation of extracellular protein deposits in the brain contributing to Alzheimer""s Disease.
The (xe2x88x92) isomer of chloroquine is an even more effective neuromelanin binders than racemic chloroquine because it breaks down less peripherally, has a longer half-life and lower clearance, and so is more available to cross the blood brain barrier, as well as having a stabilizing effect on DNA. It is therefore preferred for use in this invention.